Peptides derived from the complementarity determining region 3 (CDR3)-homologous domain of CD4, in particular CD4(81-92) and CD4(81-101), are effective anti-viral agents. Within the CD4(81-92) series, R-group derivatization nation of selective amino acid residues was an absolute requirement for biological activity. The prototype compound T1C4E5-tribenzyl-K10-acetyl-TYICEVEDQKEE inhibited HIV-1-induced cell fusion at 32 (mu)M, HIV-1 infection of CEM-SS cells at 10 (mu)M, SIV infection of CEM-174 cells at less than 125 (mu)M. gpl2O/CD4 binding at 60 (mu)M, and post infection cell-mediated viral transmission at 10-15 (mu)M. Compounds of identical structure and derivatization, but of altered primary sequence, were substantially less active, or without activity, in these assays. Peptide antiviral activity was specific, as judged by lack of cytotoxicity, lack of inhibition of HTLV-1-induced cell fusion, and lack of inhibition of CD4-dependent cellular immune function in vitro. Further derivatization of the prototype compound involving the production of cyclic congeners yielded peptides with submicromolar potency to block HIV-1 infection. Concentrations of the original prototype compound TlC4E5-tribenzyl-CD4(81-92) that inhibited infection in vitro more than 50% could be achieved for several hours by intravenous infusion in primates and were well-tolerated at these levels. The peptide was not efficacious to inhibit establishment of viral infection at these doses; however peptide treatment did lower average viral antigenemia and delay the cumulative time to morbidity relative to the control group. During the course of employing SIV-infected rhesus macaques to assess peptide safety and efficacy, animals were longitudinally tested on a battery of neurocognitive and motor tasks. Three of ten SIV-infected animals, corresponding to those with most active ongoing infection (as judged by viral antigenemia and virus rescue from peripheral blood mononuclear cells), showed relatively large decrements in performance in either motor skill or delayed matching to sample cognitive tests, suggesting the SIV-infected rhesus monkey may be a model for AIDS dementia complex as well as acquired immunodeficiency syndrome itself.